Serine proteases form an important family of enzymes whose members are essential to a variety of physiological functions: digestion, blood coagulation, lysis of blood clots, and sperm penetration. These enzymes possess a common structural feature in their active sites known as the "charge-relay chain." Previous chemical models have neglected the orientation of the carboxylate in the Asp-His part of the chain. This research plan proposes to synthesize molecules which begin to accurately represent the geometry Asp-His couple in the active site. Once synthesized, the models will be compared to the enzymes by kinetic and structural methods. This plan represents the initial step towards a long-range goal of reconstructing the active site geometry of an enzyme on a molecular framework considerably simpler than the protein yet maintaining as much as possible the identical relative orientations of the important functional groups.